MYELOID TUMORS

Current Genetic Models for Prediction of Primary Myelofibrosis

MYELOID TUMORS , , ,

LB Polushkina1, VA Shuvaev1, MS Fominykh1, YuA Krivolapov2, EA Belyakova2, ZP Asaulenko2, EV Motyko1, LS Martynenko1, MP Bakai1, NYu Tsybakova1, SV Voloshin1,3, SS Bessmeltsev1, AV Chechetkin1, IS Martynkevich1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

3 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

For correspondence: Lyubov Borisovna Polushkina, PhD in Biology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; e-mail: polushkina.lb@gmail.com

For citation: Polushkina LB, Shuvaev VA, Fominykh MS, et al. Current Genetic Models for Prediction of Primary Myelofibrosis. Clinical oncohematology. 2019;12(4):391–7 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-391-397

ABSTRACT

Aim. To study the relationship of karyotype, JAK2, CALR, and MPL driver mutations and ASXL1 mutation status with the progression and prediction of primary myelofibrosis (PMF).

Materials & Methods. The trial included 110 PMF patients (38 men and 72 women), median age was 59 years (range 18–82) with median follow-up after diagnosis of 2.6 years (range 0.1–23). The patients were examined for JAK2, CALR, MPL, and ASXL1 mutations. Restriction fragment length polymorphism technique was used for the analysis of V617F substitution in JAK2 and 515 codon mutation in MPL. CALR (exon 9) and ASXL1 (exon 12) mutation tests were performed using Sanger direct sequencing. In 48 (44 %) out of 110 patients bone marrow cell karyotype was determined. Clinical and hematological parameters and median overall survival (OS) of patients were analyzed with regard to detected genetic aberrations and combinations of them.

Results. JAK2, CALR, MPL mutations were detected in 55 (50 %), 28 (25.5 %), and 7 (6.4 %) out of 110 patients, respectively. Triple negative (TN) status was identified in 20 (18.2 %) out of 110 examined patients. ASXL1 mutations were detected in 22 (20 %) out of 110 patients. Out of 48 patients in 32 (66.7 %) normal karyotype, in 3 (6.3 %) favorable karyotype, in 4 (8.3 %) intermediate-prognosis karyotype, and in 9 (18.7 %) unfavorable karyotype were detected. The comparison of clinical and hematological parameters showed a number of significant differences. JAK2-positive patients had a higher hemoglobin level (median 129 g/L; p = 0.021). TN was associated with a high IPSS risk (p = 0.011), low hemoglobin level (median 101 g/L; p = 0.006), continuing drop in platelet count (median 266 × 109/L; p = 0.041), increased lymphocyte count (median 26.9 × 109/L; p = 0.001). The detection of terminating mutations in ASXL1 correlated with palpable enlarged spleen (p = 0.050), reduced platelet count (median 184 × 109/L; p = 0.016), leukocyte count > 25 × 109/L (p = 0.046), and blast count ≥ 1 % (p < 0.001). Univariate regression analysis showed that terminating mutations in ASXL1 (hazard ratio [HR] 2.9; p = 0.018), unfavorable karyotype (HR 8.2; p < 0.001), and TN (ОР 8.1; p < 0.001) had prognostic value for OS. ASXL1 mutation was associated with significantly worse OS in TN patients. Median OS of ASXL1-negative patients without high-risk chromosomal aberrations was significantly longer than in patients with high-risk karyotype and/or ASXL1 mutation.

Conclusion. Several genetic defects in tumor cells are associated with phenotypic manifestations of PMF. Based on the results of cytogenetic analysis and mutation determination of JAK2, CALR, MPL, and ASXL1, patients can be classified in different “genetic” risk groups when PMF is diagnosed.

Keywords: primary myelofibrosis, mutations, karyotype, prediction.

Received: April 8, 2019

Accepted: September 1, 2019

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REFERENCES

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Cerebrovascular Disorders Associated with Ph-Negative Myeloproliferative Diseases

MYELOID TUMORS , , , , ,

MM Tanashyan1, PI Kuznetsova1, AL Melikyan2, AA Raskurazhev1

1 Research Center of Neurology, 80 Volokolamskoe sh., Moscow, Russian Federation, 125367

2 National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Polina Igorevna Kuznetsova, MD, PhD, 80 Volokolamskoe sh., Moscow, Russian Federation, 125367; Tel.: +7(495)490-24-05, +7(926)142-46-48; e-mail: angioneurology0@gmail.com

For citation: Tanashyan MM, Kuznetsova PI, Melikyan AL, Raskurazhev AA. Cerebrovascular Disorders Associated with Ph-Negative Myeloproliferative Diseases. Clinical oncohematology. 2019;12(4):398–405 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-398-405

ABSTRACT

Background. Cerebrovascular disorders continue to be among the most common and socially significant worldwide. Among multiple reasons for circulatory disturbances special importance is attached to hemorheology and hemostasis disorders occurring also in patients with Ph-negative myeloproliferative diseases (MPD).

Aim. To investigate typical characteristics of the course of cerebrovascular disorders in patients with Ph-negative MPD.

Materials & Methods. The trial included 169 adult patients with neurological diseases. Among them the main group consisted of 104 patients aged 34 to 55 years (median 48.5 years) with Ph-negative MPD diagnosed at the National Medical Hematology Research Center. The control group consisted of 65 patients aged 51 to 58 years (median 55.5 years) with cerebrovascular diseases without concomitant hematological pathology.

Results. The incidence of acute ischemic strokes was 26.2 % in polycythemia vera (PV), 20.5 % in essential thrombocythemia (ET), and 8.7 % in primary myelofibrosis (PMF).

Conclusion. An acute ischemic stroke with a concurrent thrombotic occlusion of one of the major head arteries is a criterion for ruling out Ph-negative MPD. To identify cerebral lesions in patients with Ph-negative MPD (PV, ET, PMF) MRI of the brain is recommended.

Keywords: cerebrovascular diseases, myeloproliferative diseases, thrombotic complications, hemorheology, hemostasis, ischemic stroke.

Received: February 13, 2019

Accepted: September 8, 2019

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WT1 Gene Overexpression in Differential Diagnosis of Ph-negative Myeloproliferative Disorders

MYELOID TUMORS , , , ,

EG Lomaia1, NT Siordiya1, EG Lisina2, OM Senderova3, AA Silyutina1, AYu Zaritskey1

1 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

2 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

3 Irkutsk Regional Clinical Hospital, 100 Yubileinyi microdistrict, Irkutsk, Russian Federation, 664049

For correspondence: Nadiya Tamazovna Siordiya, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(921)358-31-32; e-mail: siordian@list.ru

For citation: Lomaia EG, Siordiya NT, Lisina EG, et al. WT1 Gene Overexpression in Differential Diagnosis of Ph-Negative Myeloproliferative Disorders. Clinical oncohematology. 2019;12(3):297–302 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-297-302

ABSTRACT

Aim. To assess the rate of WT1 gene overexpression and its clinical value in Ph-negative myeloproliferative disorders (MPD).

Materials & Methods. The trial included 72 patents with Ph-negative MPD. Among them there were patients with primary myelofibrosis (MF; n = 32), post-polycythemia vera MF (n = 7), polycythemia vera (PV; n = 17), and essential thrombocythemia (ET; n = 16) with median age of 57 years (range 19–78 years). Median (range) time from diagnosis to the date of evaluating WT1 expression in PV, ET, and MF was 9.4 (0–309), 14.4 (0–55), and 21.4 months (0–271 months), respectively. WT1 expression in terms of WT1 copies/104 ABL copies was measured by quantitative PCR.

Results. WT1 gene overexpression is revealed solely in patients with MF (in 34/39; 87 %). In PV/ET no WT1 gene overexpression was observed. Median WT1 expression in MF was 230/104 ABL copies (range 42.2–9,316.45/104 ABL copies). Sensitivity and specificity of WT1 gene overexpression in MF with respect to PV/ET were 87 % and 100 %, respectively. A distinct correlation was identified between WT1 gene expression level and spleen size, duration of the disease, blast cell count, and DIPSS risk group. WT1 gene expression level could be correlated neither with age and sex, nor with MF mutation status and leucocyte, thrombocyte, and haemoglobin levels.

Conclusion It appears that due to a high specificity and sensitivity of WT1 gene expression in MF it can be used as a marker for differential diagnosis of Ph-negative MPD. A correlation between WT1 gene expression and tumor mass in MF cannot be excluded. It is advisable to analyze the dynamics of WT1 expression level to predict the efficacy of current targeted therapy.

Keywords: WT1 gene, Ph-negative myeloproliferative disorders, myelofibrosis, polycythemia vera, essential thrombocythemia.

Received: December 27, 2018

Accepted: June 2, 2019

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Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

MYELOID TUMORS , , ,

IG Budaeva, EG Ovsyannikova, EN Goryunova, OV Kulemina, DV Zaitsev, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskey, LL Girshova

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Irina Garmaevna Budaeva, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(931)351-07-06; e-mail: irina2005179@mail.ru

For citation: Budaeva IG, Ovsyannikova EG, Goryunova EN, et al. Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Clinical oncohematology. 2019;12(3):289-96 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-289-296

ABSTRACT

Aim. To assess the efficacy of FLAG/FLAG-Ida regimen and to identify factors that influence remission, duration of disease-free survival (DFS) and overall survival (OS) of patients with relapsed/refractory acute myeloid leukemia (AML).

Materials & Methods. The trial included 54 patients (28 men and 26 women), median age was 37 years (range 18–70 years). 27 (50 %) out of 54 patients had refractory AML and 27 (50 %) patients had relapsed AML. FLAG and FLAG-Ida regimens were administered as induction therapy. 37 (68.5 %) patients received bone marrow transplantation. Molecular genetic and cytogenetic examinations were performed prior to therapy and on the 28th day after the start of treatment. WT1 gene expression was evaluated on the 14th–16th day of treatment.

Results. Complete remission (CR) was achieved in 42 (77.8 %) out of 54 patients. Refractoriness to therapy was observed in 9 (16.7 %) out of 54 patients, mortality was 5.5 % (3/54). Remission rate was higher in patients with relapsed AML compared with refractory AML: 85.2 % (23/27) and 70.4 % (19/27), respectively. On the 14th–16th day of treatment patients with blast cell count ≥ 10 % in bone marrow (BM) showed significantly lower CR rate (60 %) compared with the group of patients with < 10 % blast cells in BM (89.6 %; p = 0.024) and shorter DFS (median 7.6 vs. 17.6 months, respectively; p = 0.03). Median DFS in patients with WT1 expression reduction to < 1 log on the 14th–16th day was 5 vs. 18 months in patients without WT1 expression reduction (p = 0.01). DFS varied in groups of patients with blast cell count < 10 % in BM on the 14th–16th day of treatment based on the level of WT1 expression reduction (p = 0.04). MRD-negative patients (57.1 %) showed significantly longer DFS and OS compared with MRD-positive patients (median DFS was 17.6 vs. 5.2 months, respectively, p = 0.02; median OS was 19 vs. 6.9 months, p = 0.0002). Median DFS and OS were different only in ELN low- and high-risk groups (median not reached vs. 5.2 months, respectively, p = 0.039; median not reached vs. 10.2 months, p = 0.039).

Conclusion. FLAG and FLAG-Ida are effective and safe regimens in the treatment of relapsed/refractory AML. Achieving remission depends on neither the risk group nor the time of relapse occurrence. The blast cell count in BM on the 14th–16th day of FLAG/FLAG-Ida treatment is a prognostic factor determining achievement and duration of remission. WT1 expression level in the early post-induction period is a sensitive DFS marker. MRD status and molecular genetic risk (ELN) group affiliation are essential prognostic factors determining DFS and OS.

Keywords: acute myeloid leukemia, relapse, refractoriness, FLAG and FLAG-Ida regimens.

Received: November 2, 2018

Accepted: May 28, 2019

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Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany)

MYELOID TUMORS , , , ,

EV Motyko1, OV Blau2, LB Polushkina1, LS Martynenko1, MP Bakai1, NYu Tsybakova1, YuS Ruzhenkova1, EV Kleina1, NB Pavlenko1, AM Radzhabova1, EV Karyagina3, OS Uspenskaya4, SV Voloshin1, AV Chechetkin1, IS Martynkevich1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

3 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

4 Leningrad Regional Clinical Hospital, 45–49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Ekaterina Vadimovna Motyko, PhD in Biology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)925-05-62; e-mail: genetics.spb@mail.ru

For citation: Motyko EV, Blau OV, Polushkina LB, et al. Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany). Clinical oncohematology. 2019;12(2):211–9.

DOI: 10.21320/2500-2139-2019-12-2-211-219

ABSTRACT

Aim. To analyze the effect on prognosis of mutations that are typical of acute myeloid leukemia (AML) patients.

Materials & Methods. The study included 620 AML patients surveyed at Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Berlin, Germany). G-banding of chromosomes was employed for cytogenetic testing. Aberration screening in DNMT3A, IDH1/2 genes was based on real-time polymerase chain reaction (PCR) with subsequent analysis of melting and sequencing profiles. Mutations in FLT3, NPM1 genes were revealed by PCR.

Results. Mutations were identified in 343 (55.3 %) out of 620 patients. Significantly more often mutations were discovered in patients with normal karyotype (NK) (p = 0.001). FLT3-ITD mutation was associated with reduced medians of overall survival (OS) and disease-free (DFS) survival: 11.3 vs. 15.8 months with FLT3-ITD– (p = 0.005) and 10.0 vs. 13.3 months with FLT3-ITD+ (p = 0.009), respectively. The relation of FLT3-ITD allele burden to OS duration was also assessed. In the ITDlow/ITD– group the OS median was considerably longer than in the ITDhigh group (p = 0.028). In the group of patients with 1 mutation in NPM1 gene OS and DFS were much better in comparison with other patients (medians of 27.4 and 13.9 months, respectively, p = 0.040; 19.3 and 12.0 months, p = 0.049). Negative impact of mutations in DNMT3A gene was noticed while assessing OS median: 12 (DNMT3A+) and 15 months (DNMT3A–), respectively (p = 0.112). Mutations in IDH1 gene correlated with a better OS than in the group without mutations (p = 0.092). The rs11554137 polymorphism in IDH1 gene was associated with worse OS in the group of patients with NK (p = 0.186). In 144 patients various mutation combinations (from 2 to 5) were identified. It was demonstrated that mutations in FLT3 (FLT3-ITD), NPM1, DNMT3A, and IDH2 were identified significantly more often in combinations with other mutations (p = 0.001): NPM1+/FLT3-ITD+ (20.8 %), NPM1+/FLT3-ITD+/DNMT3A+ (8.3 %), and FLT3-ITD+/DNMT3A+ (8.3 %). Patients with 1 mutation had a noticeably longer OS median compared with patients with 2 mutations (18.1 and 12.2 months; p = 0.003). In patients with NPM1+ according to their OS the most unfavorable additional mutation was FLT3-ITD (median 27.4 vs. 9.2 months; p = 0.019) and the combination of NPM1+/FLT3-ITD+/DNMT3A+ (median 27.4 vs. 14.6 months; p = 0.141). OS of patients with DNMT3A+ showed a downward trend if FLT3-ITD additional mutation was identified (17.3 vs. 7.1 months; p = 0.074).

Conclusion. Mutations in FLT3, DNMT3A, IDH1/2, NPM1 genes frequently occur in AML intermediate-risk patients, i.e. they determine the intermediate prognosis group in AML. The studied mutations considerably impact prognosis. It is important to take into consideration mutation type, its allele burden, and the presence of additional mutations. A patient with 2 mutations has a considerably worse OS compared with a patient with 1 mutation. The studied group of patients with the combination of NPM1+/FLT3-ITD+, NPM1+/FLT3-ITD+/DNMT3A+, DNMT3A+/FLT3-ITD+ mutations has the poorest prognosis. Comprehensive analysis of genetic damages in AML patients allows to most accurately predict the course and prognosis of the disease and to plan targeted therapy.

Keywords: acute myeloid leukemias, mutations in FLT3, NPM1, DNMT3A, IDH1/2 genes, karyotype, prognosis.

Received: July 13, 2018

Accepted: January 16, 2019

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Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Practical Recommendations)

MYELOID TUMORS , , , , ,

EYu Chelysheva1, AG Turkina1, ES Polushkina2, MA Vinogradova2, RG Shmakov2

1 National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 VI Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 4 Akademika Oparina str., Moscow, Russian Federation, 117997

For correspondence: Ekaterina Yur’evna Chelysheva, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-48-60; e-mail: denve@bk.ru

For citation: Chelysheva EYu, Turkina AG, Polushkina ES, et al. Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Clinical Experience). Clinical oncohematology. 2019;12(2):202–10.

DOI: 10.21320/2500-2139-2019-12-2-202-210

ABSTRACT

Background. The tyrosine kinase inhibitors (TKI) era is marked by a long-term favorable prognosis of chronic myeloid leukemia (CML). In this context CML patients of reproductive age are faced with major issues of family planning with due regard to the risk of TKI treatment interruption during pregnancy. Additionally, TKI impact is another potential risk to the fetus.

Aim. To develop differentiated approach to CML treatment during pregnancy.

Materials & Methods. Analysis includes literature data and clinical experience based on 166 pregnancies of 120 CML patients from CML Pregnancy Registry.

Results. Pregnancy planning is recommended after achieving stable and deep molecular response (with BCR-ABL > 0.01 %, IS) within the period of at least 2 years. At conception TKI therapy does not have to be interrupted. However, early pregnancy detection and TKI treatment interruption after pregnancy confirmation are of vital importance due to teratogenic risks. Furthermore, no TKI may be administered during organogenetic period, i.e. up to the 15th week of gestation. In the absence or loss of complete hematologic response and growth of BCR-ABL > 1 % after the 15th week of gestation imatinib or nilotinib administration is justified in the interest of pregnant patients taking into account limited transfer of these drugs through placenta. In the absence of complete hematologic response before the 15th week of gestation interferon-α can be administered. With BCR-ABL < 1 % patients can be either followed-up without therapy or they can receive interferon-α throughout pregnancy. Dasatinib, bosutinib, and other TKI are contraindicated at any stage of pregnancy. There are no special recommendations for childbirth, delivery is to be adapted to obstetric conditions. Breast feeding is not recommended because of the lack of practical evidence for its safety.

Conclusion. A regular molecular monitoring of BCR-ABL and hematologic status is indispensable, health condition of fetus should be continuously monitored as well. CML patient management should be conducted by cooperating hematologists and gynecologists.

Keywords: chronic myeloid leukemia, pregnancy, tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib, bosutinib.

Received: January 9, 2019

Accepted: March 20, 2019

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Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ)

MYELOID TUMORS , ,

OA Shukhov, AG Turkina, EYu Chelysheva, AV Bykova, AN Petrova, GA Gusarova, IS Nemchenko, AO Abdullaev, TN Obukhova, AB Sudarikov

National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Oleg Aleksandrovich Shukhov, MD, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: shuhov@list.ru

For citation: Shukhov OA, Turkina AG, Chelysheva EYu, et al. Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ). Clinical oncohematology 2019;12(2):194–201.

DOI: 10.21320/2500-2139-2019-12-2-194-201

ABSTRACT

Background. Current clinical guidelines on diagnosis and treatment of chronic myeloid leukemia (CML) define indications for substitution of first-line tyrosine kinase inhibitor (TKI) at therapy failure during different phases of disease progression.

Aim. To assess the efficacy of CML treatment with implementing the protocol of timely monitoring and switching to another TKI.

Materials & Methods. Patients were included into pilot prospective study РИТМ during 5 years. Data on 100 CML patients were analyzed. Therapy and monitoring were conducted according to the Federal clinical guidelines on CML diagnosis and therapy, 2013.

Results. Median follow-up after initiation of treatment was 46 months (range 12–74). Imatinib mesylate was administered as first-line therapy to 91 (91 %) patients, 9 (9 %) patients received 2nd generation TKI (TKI2). Therapy failure was registered in 31 (31 %) patients; 26 (84 %) of them were switched to TKI2. At the time of analysis 95 (95 %) patients were followed-up. Cumulative incidence of CML-associated mortality was 2 %. By the fifth year of follow-up cumulative probability of complete cytogenetic, major and deep molecular responses was 93 %, 88 % and 66 %, respectively.

Conclusion. CML treatment according to current guidelines yields the results comparable with those achieved by first-line TKI2 therapy. This approach reduces CML treatment costs and lowers the risk of TKI2-associated adverse events. Due to a high rate of deep molecular response the proportion of CML patients in remission without treatment can be increased in the future.

Keywords: chronic myeloid leukemia, monitoring, tyrosine kinase inhibitors, TKI switch.

Received: October 21, 2018

Accepted: February 4, 2019

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Expression of the BCR-ABL1 Gene in Patients with Chronic Myeloproliferative Diseases with Signs of Progression

MYELOID TUMORS , , , , ,

LA Kesaeva1, EN Misyurina2, DS Mar’in2, EI Zhelnova2, AYu Bulanov2, AE Misyurina3, AA Krutov4, IN Soldatova4, SS Zborovskii4, VA Misyurin1,4, VV Tikhonova1, YuP Finashutina1, ON Solopova1, NA Lyzhko1, AE Bespalova1, NN Kasatkina1, AV Ponomarev1, MA Lysenko2, AV Misyurin1,4

1 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

3 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

4 GenoTekhnologiya, 104 Profsoyuznaya str., Moscow, Russian Federation, 117485

For correspondence: Andrei Vital’evich Misyurin, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)612-80-38; e-mail: and@genetechnology.ru

For citation: Kesaeva LA, Misyurina EN, Mar’in DS, et al. Expression of the BCR-ABL1 Gene in Patients with Chronic Myeloproliferative Diseases with Signs of Progression. Clinical oncohematology. 2018;11(4):354–9.

DOI: 10.21320/2500-2139-2018-11-4-354-359

ABSTRACT

Background. The V617F mutation of JAK2 is known to manifest in Ph-negative chronic myeloproliferative diseases (cMPD), such as polycythemia vera, thrombocythemia, and myelofibrosis. These diseases not infrequently advance into more aggressive forms up to acute leukemia. As the progression mechanism is still unknown, its study retains a high priority. JAK2 carrying the V617F mutation is believed to cause constant activation of V(D)J recombinase in myeloid tumor cells in cMPD patients. Aberrant activation of V(D)J recombinase in tumor cells in cMPD patients can lead to t(9;22)(q34;q11) chromosomal rearrangement.

Aim. To study the expression of BCR-ABL1 resulting from translocation t(9;22)(q34;q11) in cMPD patients at the progression stage in order to test the suggested hypothesis.

Materials & Methods. The BCR–ABL1 expression was assessed in peripheral blood granulocytes in cMPD patients by real-time PCR. The JAK2 V617F mutation was identified by quantitative allele-specific PCR. The JAK2 exon 12 mutations were determined using Sanger direct sequencing of PCR products.

Results. The BCR-ABL1 expression was discovered in 29 % of patients with cMPD progression. The BCR-ABL1 expression in these patients correlated with hepatosplenomegaly and hyperleukocytosis.

Conclusion. In a significant proportion of cMPD patients the disease progression can be associated with activation of the BCR-ABL expression.

Keywords: JAK2 V617F, BCR-ABL1, V(D)J recombinase, t(9;22)(q34;q11), polycythemia vera, essential thrombocythemia, myelofibrosis, chronic myeloid leukemia.

Received: April 2, 2018

Accepted: August 5, 2018

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Epidemiology of Chronic Myeloid Leukemia in the Republic of Bashkortostan

MYELOID TUMORS , , , ,

NR Ryabchikova, GSh Safuanova, VI Nikulicheva

Bashkir State Medical University, 3 Lenina str., Ufa, Russian Federation, 450008

For correspondence: Prof. Guzyal’ Shagbanovna Safuanova, MD, PhD, 3 Lenina str., Ufa, Russian Federation, 450008; Tel.: +7(927)639-03-73; e-mail: safuanova@bk.ru

For citation: Ryabchikova NR, Safuanova GSh, Nikulicheva VI. Epidemiology of Chronic Myeloid Leukemia in the Republic of Bashkortostan. Clinical oncohematology. 2018;11(4):349–53.

DOI: 10.21320/2500-2139-2018-11-4-349-353

ABSTRACT

Background. The planning of therapeutic, diagnostic, and preventive medical care for chronic myeloid leukemia (CML) patients implies the need of not only maintaining patient registries, but also conducting epidemiologic studies in each geographical area.

Aim. To study and analyze CML epidemiological indicators over the last 15 years in the Republic of Bashkortostan for the purposes of evaluation and rational planning of specialized medical care for CML patient population.

Materials & Methods. The incidence, prevalence, and mortality of CML patients of all age groups in the period of 2000–2016 was analyzed in the Republic of Bashkortostan.

Results. The analysis of epidemiological indicators over the period of 2000–2016 showed that the incidence of the disease in the Republic of Bashkortostan was increasing. Within the last 8 years the prevalence rate even quadrupled which is clearly connected with improved detectability of Ph-chromosome and/or BCR-ABL gene, creation and maintenance of CML patient registry since 2008, introduction of treatment using tyrosine kinase inhibitors resulting also in increase in life expectancy. Mortality rates are reported to have a tendency of decrease over the period under study.

Conclusion. Key epidemiological indicators of CML in the Republic of Bashkortostan are comparable with the data of international and Russian researchers. The results obtained can be used for comparative studies and improvement of specialized medical care for CML patients.

Keywords: chronic myeloid leukemia, epidemiology, incidence, prevalence, mortality.

Received: April 9, 2018

Accepted: August 3, 2018

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Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016)

MYELOID TUMORS , , ,

VV Tikhonova1,2, MA Isakov3, VA Misyurin1, YuP Finashutina1,2, LA Kesaeva1,2, NA Lyzhko 1, IN Soldatova2, NN Kasatkina1, EN Misyurina4, AV Misyurin1,2

1 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 GenoTekhnologiya, 104 Profsoyuznaya str., Moscow, Russian Federation, 117485

3 Aston Consulting, 31g Shabolovka str., Moscow, Russian Federation, 115162

4 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

For correspondence: Vera Vyacheslavovna Tikhonova, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(967)008-02-84; e-mail: brilfor@mail.ru

For citation: Tikhonova VV, Isakov MA, Misyurin VA, et al. Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016). Clinical oncohematology. 2018;11(3):227–33.

DOI: 10.21320/2500-2139-2018-11-3-227-233

ABSTRACT

Background. Kinase domain mutations of BCR-ABL gene is the most common cause of tyrosine kinase inhibitor resistance.

Aim. To present the data on prognostic value of BCR-ABL mutation burden in Russian patients over the last 10 years.

Materials & Methods. The study included 1885 chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitor resistance who were followed up from 2006 to 2016. BCR-ABL point mutations in mRNA samples were analyzed by means of polymerase chain reaction and subsequent Sanger sequencing.

Results. In 1257 CML patients with signs of tyrosine kinase inhibitor resistance BCR-ABL expression level was > 1 %. BCR–ABL mutations were detected in 31.8 % of patients. Total mutation count was 467 (70 mutation types). Total count of patients with mutation-associated tyrosine kinase inhibitor resistance decreased from 36.6 % (2006–2008) to 24.95 % (2013–2016) and to marked decrease of 23.12 % in 2014. Detection rate of imatinib-resistant mutations and F359V mutation was shown to decrease within the period from 2010–2011 to 2014–2015. F317L level, which is responsible for dasatinib resistance, considerably increased in 2015. T315I frequency was the highest in 2014, afterwards it was gradually decreasing. Mutation-associated resistance rates varied by region of the Russian Federation.

Conclusion. The analysis of trends of mutation incidence in patients with CML can be of extreme significance in long-term prognosis of resistance development and in improvement of treatment planning.

Keywords: chronic myeloid leukemia, kinase domain mutations of BCR-ABL gene, targeted therapy, resistance.

Received: January 22, 2018

Accepted: April 16, 2018

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